Back to Search
Start Over
Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 May 01; Vol. 16 (9), pp. 2380-6. Date of Electronic Publication: 2006 Feb 14. - Publication Year :
- 2006
-
Abstract
- Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (L-alpha,beta-diaminopropionic acid) residue. At the P1' position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood-brain barrier. Herein, we report BACE1 inhibitors with P1' carboxylic acid bioisosteres in order to develop practical anti-Alzheimer's disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50=4.8 nM) and KMI-684 (IC50=1.2 nM), exhibited significantly potent BACE1 inhibitory activities.
- Subjects :
- Alzheimer Disease drug therapy
Amyloid Precursor Protein Secretases
Crystallography, X-Ray
Drug Evaluation, Preclinical
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Models, Molecular
Molecular Structure
Oligopeptides chemistry
Oligopeptides pharmacology
Stereoisomerism
Structure-Activity Relationship
Carboxylic Acids chemistry
Drug Design
Endopeptidases drug effects
Enzyme Inhibitors chemical synthesis
Oligopeptides chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0960-894X
- Volume :
- 16
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 16481167
- Full Text :
- https://doi.org/10.1016/j.bmcl.2006.01.108